Tailoring buchwald-type phosphines with pyrimidinium betaines as versatile aryl group surrogates

Article abstract of DOI:10.1021/om5007819

A derivatization of dialkylbiarylphosphines consisting in the formal replacement of their distal aryl group by a pyrimidinium betaine is reported. Two achiral representatives of this new class of Buchwald-type phosphines have been successfully synthesized through two strategies. The first one is based on a last stage introduction of the phosphino moiety, and the second one consists in a modular, one-pot, three-step procedure starting from an o-bromoaryl phosphine. The resulting phosphines have been coordinated onto gold(I) and palladium(II) centers and have been employed as supporting ligands in Pd-catalyzed Suzuki-Miyaura cross-coupling of aryl halide substrates.

Full text of DOI:10.1021/om5007819

Communication
pubs.acs.org/Organometallics
Tailoring Buchwald-Type Phosphines with Pyrimidinium Betaines as
Versatile Aryl Group Surrogates
Ludovik Noel-Duchesneau,†,‡ Noel Lugan,†,‡ Guy Lavigne,†,‡ Agnes Labande,*,†,‡ and Vincent Cesar*,†,‡
̀
́
̈
̈
†CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, F-31077 Toulouse, Cedex 4, France
‡Universite
́
de Toulouse, UPS, INPT, 31077 Toulouse, France
S
* Supporting Information
ABSTRACT: A derivatization of dialkylbiarylphosphines consisting in the formal
replacement of their distal aryl group by a pyrimidinium betaine is reported. Two achiral
representatives of this new class of Buchwald-type phosphines have been successfully
synthesized through two strategies. The first one is based on a last stage introduction of the
phosphino moiety, and the second one consists in a modular, one-pot, three-step procedure
starting from an o-bromoaryl phosphine. The resulting phosphines have been coordinated
onto gold(I) and palladium(II) centers and have been employed as supporting ligands in
Pd-catalyzed Suzuki−Miyaura cross-coupling of aryl halide substrates.
Chart 1. Design and Structure of the Target Pyrimidinium
Betaine-Containing Phosphine
dvances in transition metal catalysis are often linked to the
Ainnovative design of modulable ligands. Indeed, a suitable
tailoring of the ligand architecture is crucial to ensure optimum
steric protection and/or stereoelectronic control of the catalytic
species and to provide low activation energy pathways for
challenging transformations.1,2 As illustrative example, mono-
dentate, bulky, and electron-rich dialkylbiarylphosphines, first
introduced in 1998 by Buchwald,3 have revolutionized Pd-
catalyzed cross-coupling4 and have also found extensive utility
in homogeneous gold catalysis,5 often serving as a source of
inspiration for many researchers. In particular, efficient chiral
monodentate phosphines6 derived from such a platform include
binaphthyl-based phosphines such as MOP and KenPhos,7 P-
chirogenic [1,3]-oxaphospholines,8 chiral P-(o-biaryl)-
phospholanes,9 and enantiopure 2-(imidazolidinon-2-yl)-
phenylphosphines.10 They remain relatively rare, which
undoubtedly reflects a real general difficulty to convert an
efficient achiral structural motif into its chiral equivalent. With
this in mind, we reasoned that pyrimidinium betaines, which
are the precursors of our previously reported anionic N-
heterocyclic carbenes (NHCs),11,12 present beneficial features
to constitute potentially suitable chiral mimics of aryl groups.
Indeed, these globally neutral, mesoionic, six-membered
heterocycles are planar and stable against air and moisture
and their synthesis is well documented.13 Moreover, given that
they are readily accessible from primary amines, implementa-
tion of their chiral congeners from chiral primary amines could
easily be envisioned.
We report here our progress toward the synthesis of an
achiral representative of this new ligand class, its ability to
coordinate transition metal centers, and preliminary catalytic
studies demonstrating its potential as ancillary ligand.
Isopropylamine was chosen for this study since it appears to
be a good achiral analogue of chiral amines possessing an
asymmetric α-carbon atom such as the (R)- or (S)-1-
phenylethylamine. Two strategies have been designed for the
synthesis of the targeted phosphine ligands. The first one is
based on a late-stage introduction of the phosphino moiety
from the key intermediate 3 (Scheme 1). The latter was
obtained from 2-bromobenzoic acid through a three-step
sequence consisting of the amidation of 2-bromobenzoic acid
leading to 1, the subsequent activation of the amide moiety and
the addition of a second amine to generate amidine 2, and the
final cyclization by coupling 2 with methylmalonyl dichloride
through a double peptide-type coupling. Compound 3 is air
and water stable and was fully characterized. In particular,
evidence for the formation of the heterocycle was inferred from
the appearance of a signal at δ = 96.9 ppm in the 13C NMR
spectrum assigned to the central malonate carbon atom (C5)
In a first approach, we projected the substitution of the distal
aryl group of a Buchwald-type phosphine by a pyrimidinium
betaine moiety, with the objective to obtain a new tunable
ligand class with interesting potential (Chart 1), considering
that the specific arrangement of the ligand would put the chiral
groups in suitable close proximity to the metallic center,
defining a precise chiral space around the latter.
Received: July 30, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om5007819 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
C
sp2 −N sp2 bonds (1.45−1.47 Å).15 The 2-
Scheme 1. Synthesis of Phosphine 4a Based on the Final
Introduction of the Phosphino Moiety
(diphenylphosphino)phenyl and heterocycle moieties are
roughly orthogonally arranged around their C1−C12 con-
nection (dihedral angle N1−C1−C12−C13: 100.16°), as
expected for a Buchwald-type phosphine. Most notably, the
observed conformation of 4a in the solid state, with the lone
pair of the phosphorus atom pointing toward the upper side of
the pyrimidinium betaine and the C−H bonds of the isopropyl
substituents pointing toward the 2-(diphenylphosphino)phenyl
group, may result from the minimization of the steric
constraint, validating our first hypothesis.
Although quite efficient, the latter synthetic pathway suffers
from its high number of steps and purifications. We thus
decided to develop a more straightforward, modular procedure
in view of a future rapid optimization of the ligand structure for
catalytic applications (Scheme 2). Starting from the readily
Scheme 2. One-Pot, Two-Step Synthesis of Phosphines
a
4a,b
characteristic of pyrimidinium betaine rings. Whereas first tests
of Br/Li exchange on 3 using nBuLi or tBuLi led to intractable
mixtures, we were pleased to find that Br/Mg exchange
smoothly occurred using Knochel’s isopropylmagnesium
chloride lithium chloride complex iPrMgCl·LiCl, giving clean
and quantitative transmetalation in less than 30 min
(conversion determined after hydrolysis of the crude
product).14 Further addition of chlorodiphenylphosphine
provided the phosphine 4a in 66% yield after column
chromatography.
a
DIC: N,N′-diisopropylcarbodiimide.
Phosphine 4a is fully air stable in the solid state and
moderately sensitive toward oxidation in solution. Its
formulation was confirmed by spectroscopic and analytical
methods. The 31P signal of the phosphorus atom appears at δ =
−17.8 ppm in the 31P{1H} NMR spectrum. The molecular
structure of 4a was confirmed by an X-ray crystal structure
determination (Figure 1). As previously observed,11 the
pyrimidinium betaine ring is almost perfectly planar and
consists of two independent π systems, namely, a four-π-
electron amidinium moiety on which a six-π-electron malonate
backbone is grafted via the N1−C2 and N2−C4 bonds, whose
average length (1.45 Å) falls in the range of prototypical single
available (2-bromophenyl)phosphines 5a,b,16 the amidines 6a,b
were obtained by bromine−lithium exchange using nBuLi
followed by nucleophilic addition onto N,N′-diisopropylcarbo-
diimide (DIC) and final reprotonation with HCl. The amidines
6a,b were used directly in the next cyclization step with
methylmalonyl dichloride. Noteworthy, the protonation step
was found to be crucial for the procedure since the direct
coupling between basic amidinates and methylmalonyl
dichloride led to considerable amounts of decomposition
products, probably due to undesired deprotonation of the
malonyl moiety. The target phosphines 4a,b were isolated in
39% and 42% yields, respectively, after simple-column
chromatography.17 Being quick and operationally simple, the
strategy appears quite promising for the development of a
library of chiral monodentate phosphines, especially as chiral
carbodiimides are easily obtained from the corresponding chiral
amines in two steps.18
To estimate the coordination ability of phosphines 4a,b, we
next prepared their gold(I) and palladium(II) complexes
(Scheme 3).
Mixing ligand 4a and AuCl(tht) in CH2Cl2 at room
temperature led to the complete formation of complex 7 in
less than 30 min as judged by 31P{1H} NMR with a downfield
shift of the phosphorus atom from δ = −17.8 ppm in the free
phosphine to δ = 21.9 ppm in the complex. In the solid state,
complex 7 exhibits the typical linear coordination geometry of
gold(I) complexes [P1−Au1−Cl1: 177.87(2)°] (Figure 2),
adopting a conformation where the AuCl unit lies above the
pyrimidinium betaine ring. More specifically, the gold center
Au1a is positioned above the ipso carbon C1a of the amidinium
ring. The Au1−C1 distance of 3.145 Å is smaller than the sum
of the van der Waals radii (∼3.36 Å)19 and lies in the range of
typical Au−Cipso distances in neutral Buchwald-type phos-
Figure 1. Molecular structure of 4a (ellipsoids drawn at the 30%
probability level). Hydrogen atoms have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): C1−N1 1.337 (2), C1−
N2 1.335(2), N1−C2 1.452 (2), N2−C4 1.451 (2), C2−C3 1.393(2),
C3−C4 1.399(2), C2−O1 1.230(2), C4−O2 1.236(2), P1−C13 1.838
(2), P1−C18 1.831(2), P1−C24 1.839(2), N1−C1−C12−C13
100.16.
B
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Communication
Scheme 3. Preparation of the Gold(I) and Palladium(II)
a
Complexes 7 and 8
Figure 3. X-ray structure of complex 8 (ellipsoids displayed at 30%
probability). Hydrogen atoms have been omitted for clarity. Selected
bond lengths (Å) and angles (deg): Pd1−P1 2.3148(4), Pd1−Cl1
2.3808(5), Pd1−C24 2.112(2), Pd1−C25 2.1567(18), Pd1−C26
2.2053(19), P1−Pd1−Cl1 90.819(16), P1−Pd1−C24 103.21(6),
C24−Pd1−C26 67.92(9), C26−Pd1−Cl1 97.45(7).
a
tht = tetrahydrothiophene.
point toward the aryl group, is the result of the minimization of
the steric energy.
In a preliminary evaluation of the catalytic activities of
phosphines 4a,b as supporting ligands in the Suzuki−Miyaura
coupling of substituted aryl halogenides with phenyl boronic
acid, classical conditions were chosen (DME as the solvent,
Cs2CO3 as the base, and a reaction temperature of 80 °C)
(Table 1). The catalyst was generated in situ by mixing
Table 1. Pd-Catalyzed Suzuki−Miyaura Coupling between
Phenyl Boronic Acid and Several Aryl Halides Using 4a,b as
a
Supporting Ligands
Figure 2. X-ray structure of complex 7 (ellipsoids displayed at 30%
probability). Solvent molecule and hydrogen atoms have been omitted
for clarity. Selected bond lengths (Å) and angles (deg): Au1−P1
2.2280(12), Au1−Cl1 2.2796(13), Au1−C1 3.145, P1−Au1−Cl1
177.87(2), Au1−P1−C12−C1 12.68.
b
entry
ligand
X
R
yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4a
4b
4b
4a
4b
4b
4b
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
4-Me
96
4-Me
97
88
90
90
57
63
phine/gold(I) complexes (3.12−3.25 Å),20 suggesting a weak
attractive interaction between both atoms. The Au1−P1
coordination bond is twisted relative to the C1−C12 bond
[dihedral angle Au1−P1−C12−C1: 11.09°], while a slight
distortion from planarity of the heterocycle is observed.
4-OMe
4-OMe
2-Me
4-NO2
4-NO2
4-COMe
4-Me
Complex [(4b)PdCl(allyl)] (8) was obtained through a
classical complexation procedure, namely by reaction of
phosphine 4b with the [PdCl(allyl)]2 dimer, and was isolated
in 48% yield after crystallization. Interestingly, whereas both 1H
and 13C NMR spectra display only one well-defined set of
signals for complex 8, one small singlet at δ = −3.3 ppm
assigned to free 4b is observed in the 31P NMR spectrum
besides the signal at δ = 60.8 ppm for 8. This suggests the
occurrence of an equilibrium between free 4b and complex 8, as
confirmed by a 2D 31P−31P EXSY experiment revealing the
existence of cross-peaks between the two signals. In the solid-
state structure, the PdCl(allyl) moiety was found opposite the
pyrimidinium betaine, probably due to a strong steric repulsion
between this bulkier metallic fragment (compared to the AuCl
fragment) and the isopropyl substituents of the nitrogen atoms
(Figure 3). Complex 8 displays a distorted square planar
coordination geometry typical of η3-allyl palladium(II)
complexes. Here again, the preferred conformation of the
isopropyl groups on nitrogen atoms, where the C−H bonds
26
c
<10% conv
a
Reaction conditions: aryl halide (0.5 mmol), phenyl boronic acid (1.5
equiv), Cs2CO3 (2.0 equiv), [PdCl(cinnamyl)]2 (2 mol %), ligand (4
mol %), DME (0.5 mL), 80 °C, 15 h. Yields refer to the average of
isolated yields of two runs after chromatography. Conversion
b
c
determined by GC.
[PdCl(η3-cinnamyl)]2 (2 mol %) and phosphines 4a,b (4 mol
%). Generally, the electron-rich phosphine 4b was found to be
slightly more efficient than the triarylphosphine 4a (entries 1−
4, 6, 7). While both systems gave very good isolated yields of 4-
methyl- and 4-methoxybiphenyl, switching to the more
challenging aryl chlorides allowed an estimate of the limits of
their catalytic efficiency. While 4-nitrochlorobenzene and 4-
chloroacetophenone were coupled with phenyl boronic acid in
moderate isolated yields (entries 6−8), only low conversion
was observed for the nonactivated 4-chlorotoluene (entry 9).
C
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Communication
Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.;
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In summary, we have validated an efficient modular synthetic
strategy to a new class of Buchwald-type phosphines,
incorporating a mesoionic pyrimidinium betaine ring in their
structure. Coordination on gold(I) and palladium(II) centers
has been achieved, whereas our preliminary tests of the latter
complexes in Pd-catalyzed cross-coupling are testimony to the
potential of these phosphines in homogeneous catalysis. In a
logical extension of the present conceptual approach, the next
challenge will now be to access the chiral congeners of these
ligands from commercially available chiral amines and to
implement them in asymmetric catalysis. This work is currently
under way in our laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
́
ar, V.; Lugan, N.; Lavigne, G. Chem.Eur. J.
S
́
ar, V.; Lugan, N.; Lavigne, G. Chem.Eur. J.
ar, V.; Lugan, N. l.; Lavigne, G. J. Am. Chem.
Experimental section, full characterization data for all new
compounds, and crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
́
́
ar, V.; Tourneux, J.-C.;
́
AUTHOR INFORMATION
Corresponding Authors
*E-mail: agnes.labande@lcc-toulouse.fr.
*E-mail: vincent.cesar@lcc-toulouse.fr.
■
́
Chem. Commun. 2009, 4720.
(13) Mesomeric betaines of this type have been repeatedly described.
For a definition, see: Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A.
Tetrahedron 1985, 41, 2239.
Notes
The authors declare no competing financial interest.
(14) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333.
ACKNOWLEDGMENTS
We thank the ANR (Programme JCJC “ChirASCat” ANR-11-
JS07-010-01) and the CNRS for funding this project. Dr. Rem
Brousses is acknowledged for some X-ray diffraction studies.
■
(15) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,
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diffraction experiment is described in the SI.
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dx.doi.org/10.1021/om5007819 | Organometallics XXXX, XXX, XXX−XXX